Tri-higher alkyl tin azide and its use

ABSTRACT

Disclosed are a compound of the formula (R) 3  SnN 3 , wherein R is a C 7-18  alkyl, and a process for producing a tetrazolylbenzene compound which comprises reacting a cyanobenzene compound with a (R) 3  SnN 3 . This process is useful for a safe and commercially profitable production of the tetrazolylbenzene compound which is employed for producing a tetrazole derivative having a hypotensive action based on angiotensin II-antagonizing activity or a production intermediate thereof.

FIELD OF THE INVENTION

The present invention relates to a novel tri-higher alkyltin azide.

Further, the present invention relates to a commercially valuable andsafe process for producing tetrazolylbenzene compounds from cyanobenzenecompounds using a tri-higher alkyltin azide. More particularly, theinvention relates to a safe and commercially valuable process forproducing a tetrazole derivative having a hypotensive action based onangiotensin II-antagonizing activity or a production intermediatethereof.

BACKGROUND OF THE INVENTION

The official gazette of Japanese Patent Laid-open Publication No.1-117876/1989 discloses the process schematically illustrated below forthe production of a tetrazole intermediate for antihypertensivecompounds. ##STR1## This process comprises reacting the nitrile compoundwith an excess of trimethyltin azide, separating the crystallinetrimethyltin tetrazole derivative from the residual trimethyltin azideby filtration and removing the trimethyltin group with hydrogen chlorideto provide the desired tetrazole compound.

Japanese Patent Laid-open Publication No. 63-23868/1988 discloses thefollowing process. ##STR2##

However, Process A described above is disadvantageous, as a commercialproduction process, in that the overall yield is only 78% and theprocess involves two reaction steps. Moreover, it is likely that some ofthe excess trimethyltin azide contaminates the trimethyltin tetrazolederivative produced. It is also likely that when the trimethyltintetrazole derivative is hydrolyzed with hydrogen chloride, thecontaminant trimethyltin azide is decomposed to give rise to the toxicand highly explosive hydrogen azide. Therefore, this process as acommercial process presents a serious safety problem.

On the other hand, in Process B, the range of compatible compounds islimited as compared with the organotin azide process. For example, inthe case of a compound in which the substituent in the 2-position of theimidazole ring is a lower alkoxy group, there occurs a decompositionreaction to detract from the product yield. Moreover, since asublimation of the explosive ammonium azide [N. Irving Sax, Richard J.Lewis, Sr., Dangerous Properties of Industrial Materials, Van NostrandReinhold (1989)] occurs during the reaction to cause deposition of thesublimed azide on the condenser or reactor ceiling, the process is lesssuitable for commercial exploitation from safety points of view.

In either process, it is common practice to use the azide compound inexcess for improved yield and reduced reaction time but when thereaction mixture is acidified, the toxic and highly explosive hydrogenazide is released from the unreacted azide compound present in thereaction system.

Since this hydrogen azide is a volatile liquid (boiling point: 37° C.),it is obvious that the worker handling it is exposed to a constant risk.It is reported that hydrogen azide administered in a dose of 0.05 to 0.1mg/kg induces prostration in man. Moreover, while hydrogen azide as suchis a highly explosive substance, it is known that the presence of thissubstance even in solution at a concentration over 17% is a dangerouscause of explosion, suggesting that an organic composition or systemcontaining this substance at a substantial level is also a major sourceof hazard. It is also known that hydrogen azide forms explosive saltswith heavy metals.

Particularly when an organotin azide such as a trialkyltin azide ortriphenyltin azide is employed, the step of hydrolyzing the trialkyltinor triphenyltin tetrazole derivative with an inorganic acid to providethe tetrazole derivative requires a provision for stripping off thehydrogen azide originating from the excess organotin azide from thereaction system and trapping it with an alkaline solution, but since theprocedure involved is complicated and very dangerous, the method cannotbe utilized commercially.

Also, WO92/02508 discloses the following process. ##STR3## This processcomprises reacting the nitrile compound with tributyltin azide andremoving the tributyltin group without isolation of the tributyltintetrazole derivative by addition of aqueous mineral acid to the reactionmixture.

However, tributyltin azide is high in vapor pressure (b.p. 118°-120°C./0.18 mmHg) and has a powerful odor. This odor is an extraordinarilypeculiar one, which is readily absorbed by other materials, for example,clothes of workers, reaction vessels or drying machines, and, which,once absorbed, is hard to remove. Besides, tributyltin azide causes,once touching on the skin directly, flush area on the skin, giving riseto rash symptoms such as itching or blisters.

Further, it is known that lower alkyl tin compounds are generally highlytoxic [N. Irving Sax, Dengerous Properties of Industrial Materials(1989)]. While tributyltin azide is usually synthesized from tributyltinchloride and sodium azide, the starting tributyltin chloride has also apowerful odor and causes rashes, and its toxicity is so strong as toproduce an LD₅₀ 129 mg/kg (rats, p.o. Albright and Wilson Ltd.,Technical Service Note, "Tributyltin Chloride--Safety and EnvironmentalProtection," March, 1977). Further, tributyltin chloride is absorbedalso from the skin.

The workers using tributyltin azide are exposed to a constant risk ofhazard such as its peculiar odor absorbed into their clothes,troublesome processes of washing the machines and tools, appearance ofrash, odor of the starting material, toxicity and danger of itsabsorbance from the skin. Therefore, it is difficult to use tributyltinazide on an industrial scale, from the viewpoint that the safety of theworkers is not ensured.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a novel tri-higheralkyltin azide, which is represented by the formula (Q) or (R)₃ SnN₃,wherein R is a C₇₋₁₈ alkyl.

Another object of the present invention is to provide a process forproducing a tetrazolylbenzene compound which comprises reacting acyanobenzene compound with a compound of the formula (Q).

DETAILED EXPLANATION OF THE INVENTION

The inventors of the present invention found unexpectedly after muchresearch how to resolve the problems and to develop a commercial-scaleproduction process for the belowmentioned compound (I) that the desiredtetrazole derivative can be produced in one step with safety on acommercial scale by subjecting a suitably substituted cyanobenzenecompound (II) and an excess of the compound of the formula (Q) to a1,3-dipolar cycloaddition reaction to give a trialkyltin tetrazolederivative, adding an aqueous solution of sodium nitrite and a loweralcohol to the reaction mixture containing said derivative andacidifying the mixture with hydrochloric acid whereby the hydrogen azidederived from residual azide compound is safely decomposed without beingreleased from the reaction system and said trialkyltin tetrazolederivative is hydrolyzed without prior isolation from the reactionsystem.

Thus, when 1.5 to 3 equivalents, relative to the excess trialkyltinazide, of sodium nitrite is added to the reaction mixture prior tohydrolysis and, then, the mixture is rendered acidic for hydrolysis, thereleased hydrogen azide instantly reacts with nitrous acidquantitatively and decomposes into dinitrogen oxide, nitrogen and water.Since hydrogen azide assumes a bloody red color on admixture with anaqueous solution containing an excess of ferric salt, this colorreaction is generally used for its detection. However, this colorreaction does not take place in a solution containing nitrous acid, thatis to say the reaction mixture in which hydrogen azide has beencompletely decomposed. Thus, for the production of a tetrazolederivative using a trialkyltin azide on a commercial scale, a method forhydrolyzing such excess organotin azide with safety has been eagerlyawaited.

The present invention provides a novel trialkyltin azide of the formula(Q) useful as the agent for forming a tetrazole ring. In the formula(Q), the alkyl R includes straight-chain and branched C₇₋₁₈ alkylgroups, for example, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl,nonadecyl, eicosyl and so on, with preference given to straight-chainC₇₋₁₈ alkyl groups. Among them, alkyl groups of not more than 10 carbonatoms are the more preferred, with the most preference given to n-octyl.Trioctyltin azide in which R represents n-octyl is sparingly toxic andsubstantially odorless. Moreover, trioctyltin azide in which Rrepresents n-octyl can be used most advantageously, for it can be easilyrecovered from the reaction mixture.

The compound of the formula (Q) is produced by the method stated below:

In accordance with the method described on p.881 of Organic Synthesis,Coll. Vol. IV 1963, tetraalkyltin chloride is synthesized from alkylhalide, then, trialkyltin chloride is synthesized in accordance with themethod disclosed by G. J. M. Van Der Kerk and J. G. A. Luijten, onJournal of Applied Chemistry, 6. 93(1956). Further, by the methoddisclosed by J. G. A. Luijten et al. on Recueil des Travaux Chimiquesdes Pays-Bas, 81, 202(1962), 81, 202(1962), tri-higher alkyltin azidecan be synthesized.

The above reaction of trialkyltin chloride with sodium azide is carriedout in a solvent or no solvent. The solvent is not limited in kind,provided that it does not interfere with the reaction, although diethylether, toluene, water etc. are preferred, that is, sodium azide canreact in a suspension or in a solution. The amount of the solvent is notcritical but is preferably 0.2 times to 10 times the amount of thestarting material. The amount of sodium azide is not critical but it iseconomically advisable to use 1 to 3 equivalents based on thetrialkyltin chloride. The reaction temperature is not critical but isgenerally 2° C.-130° C. and preferably 5° C.-120° C. The reaction timeis not limited, either, but is preferably 1 to 10 hours for mostpractical purposes.

As the compound of the formula (Q) has a low vapor pressure and lessodor, it is easy to handle, and, besides, it does not cause rashes toworkers, thus being safe for them. The yield of tetrazolation issubstantially the same as or even higher than that of a tri-loweralkyltin azide. While azides are generally known as explosivesubstances, a tri-higher alkyltin azide is considered to be lessexplosive than a tri-lower alkyltin azide. This is supported also by thefact that, for example, trioctyltin azide is decomposed exothermally at303° C. while tributyltin azide is decomposed exothermally at 295° C.when measured by means of Differential Scanning Calorimeter.

And, acute toxicities of tributyltin azide were compared with those oftrioctyltin azide by oral administration to rats, resulting in that,while the LD₅₀ of tributyltin azide was 400 mg/kg in male animals and200-400 mg/kg in female animals, that of trioctyltin azide was higher,i.e. 500-1000 mg/kg in male and 250-500 mg/kg in female. In both groupsreceiving trioctyltin azide (500 mg/kg or more) and tributyltin azide(100 mg/kg or more), critical signs such as decreased activity,hyporectivity and abnormal position were observed. In addition to thesefindings, the rats receiving tributyltin azide (100 mg/kg or more)exhibited salivation (immediately after administration) and severediarrhea (2-4 days), which suggested direct local irritation by thiscompound of the gastrointestinal tracts. At necropsy, the rats receivingtributyltin azide exhibited diarrhea and showed fluid in the intestinaltracts, whereas in the rats receiving trioctyltin azide no abnormalitiesattributed to the test compound were observed except for congestion orhypermia of the lung. Therefore, trioctyltin azide was somewhat lesstoxic with respect to the mortality and LD50 value. Judging fromclinical signs and necropsy finding, tributyltin azide was more toxicthan trioctyltin azide.

The starting material of trioctyltin azide, one of the tri-higheralkyltin azides, is trioctyltin chloride, and the LD₅₀ of trioctyltinchloride is 4000 mg or higher (rats, p.o. A. Bokranz and H. Plum,"Industrial Manufacture and Use of Organotin Compounds," Schering AG,Bergkamen, W. Germany, March, 1975). Therefore, trioctyltin chloride canbe used safely even in the case of producing trioctyltin azide.Therefore, a tri-higher alkyltin azide is remarkably excellent as atetrazolating agent.

Further, the present invention provides a process for producing atetrazolylbenzene compound characterized by reacting a cyanobenzenecompound with the compound of the formula (Q) and more particularly to aprocess for producing a compound of the formula (I) which comprisesreacting a compound of the formula (II) with a compound of the formula(Q) and then acidifying the reaction mixture in the presence of nitrousacid or a salt thereof. ##STR4## wherein A represents hydrogen, aphthalimido or a group of the formula ##STR5## wherein R¹ represents analkyl group which may be substituted and bound to the imidazole ringthrough a hetero atom; R² and R³ each represents hydrogen, halogen,formyl, alkoxycarbonyl or alkyl which may be substituted by hydroxy orR² and R³ may jointly form a benzene ring in combination with the twoadjacent carbon atoms on the imidazole ring.

The cyanobenzene compound is not specifically limited, provided that itis a compound having a cyano group on a benzene ring and being capableof reacting with a trialkyltin azide of the formula (Q) to form atetrazole ring. Among such compounds, compounds of the above formula(II) are preferred.

Referring to the formula (I), R¹ is an alkyl or other group which may besubstituted and be bound through a hetero atom (e.g. --O--, --S--,--NH--), thus including lower (C₁₋₄)alkyl, lower (C₁₋₄)alkoxy, lower(C₁₋₄) alkylthio and lower (C₁₋₄)alkylamino. Particularly preferred areethoxy and butyl.

R² and R³ include hydrogen, halogen (e.g. Cl, Br, I), formyl,alkoxycarbonyl (e.g. lower (C₁₋₄)alkoxycarbonyl), alkyl which may besubstituted by hydroxy (e.g. lower (C₁₋₄)alkyl, hydroxymethyl), and soon.

Referring to the formula (II), where R² and R³ form a benzene ring,substituent groups (preferably numbering 1 or 2) on the benzene ringinclude lower (C₁₋₄)alkyl, halogen, lower (C₁₋₄)alkoxy, lower(C₁₋₄)alkoxycarbonyl, phenyl-lower (C₁₋₄)alkoxycarbonyl and so on. Thepreferred examples of A in formula (II) are groups of the formula##STR6## wherein R¹ is as defined hereinbefore; R⁴ represents hydrogenor lower (C₁₋₄)alkyl (preferably methyl, ethyl) which is optionallysubstituted with hydroxyl, amino, halogen, a lower (C₂₋₆) alkanoyloxy(e.g. acetyloxy, pivaloyloxy, etc.), 1-lower (C₁₋₆) alkoxycarbonyloxy(e.g. methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy,etc.) or a lower (C₁₋₄) alkoxy. The more preferred are groups of theformula ##STR7## wherein R⁴ is as defined above.

The trialkyltin azide of the formula (Q) is capable of reacting with acyanobenzene compound to form a tetrazole ring.

In the process of the present invention, the alkyl R of the formula (Q)includes straight-chain and branched C₇₋₁₈ alkyl groups, for example,heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl,pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl and soon, with preference given to straight-chain C₇₋₁₈ alkyl groups. Amongthem, alkyl groups of not more than 10 carbon atoms are the morepreferred, with the most preference given to n-octyl. Trioctyltin azidein which R represents n-octyl is sparingly toxic and substantiallyodorless. Moreover, trioctyltin azide in which R represents n-octyl canbe used most advantageously, for it can be easily recovered from thereaction mixture.

Referring to nitrous acid or a salt thereof, a salt of nitrous acid withan alkali metal, such as sodium or potassium, is preferred and, inparticular, sodium nitrite is advantageous. In acidifying the reactionmixture in the presence of nitrous acid or a salt thereof, the reactionmixture is preferably adjusted with an inorganic acid to pH ≦ about 4and, for still better results, to pH about 1 to 3. The inorganic acidmentioned above includes hydrochloric acid, sulfuric acid, phosphoricacid, etc., although hydrochloric acid is particularly preferred.

The above reaction is carried out in a solvent. The solvent is notlimited in kind, provided that it does not interfere with the reaction,although comparatively high-boiling organic solvents such as toluene,xylene, dimethylformamide, dimethylimidazolidinone, etc. are preferred.The amount of the solvent is not critical but is preferably 3 to 10times the amount of the starting material. The reaction temperature isgenerally 90° C. to 150° C. and preferably 100° C. to 130° C. The amountof trialkyltin azide of the formula (Q) is not critical but it iseconomically advisable to use 1 to 3 equivalents based on thecyanobenzene compound. The reaction time is not limited, either, but ispreferably 5 to 40 hours for most practical purposes. Moreover, thereaction is carried out in a one pot reaction, that is, a mixture of thecyanobenzene, trialkyltin chloride, sodium azide and the solvent isstirred under the conditions above mentioned and treated to give thedesired tetrazole derivative.

The conditions, under which the hydrogen azide formed on acidolysis ofthe trialkyltin azide is decomposed by nitrous acid or a salt thereof,are not critical but the temperature is preferably maintained between 5°C. and 40° C. Any residue of nitrous acid at the end of this treatmentindicates that the decomposition reaction has been successfullycompleted. Theoretically the amount of nitrous acid or a salt thereofneed not be over one equivalent relative to the excess azide compoundbut it is safe and economical to use 1.2 to 3 equivalents.

Because the excess azide can thus be safely decomposed by acidifying thereaction mixture in the presence of nitrous acid or a salt thereof, thetrialkyltin tetrazole derivative need not be separated from the reactionmixture and, moreover, can be easily hydrolyzed to provide thetetrazolylbenzene compound. Furthermore, the desired compound can becaused to separate out as crystals in many cases. Isolation andpurification of the tetrazolylbenzene compound can be effected by theroutine procedure (e.g. filtration, extraction, concentration,recrystallization, column chromatography, etc.). Particularly withtrioctyltin azide, the liposolubility of which is higher than that of atri-lower alkyl tin compound, it is likely that removal of the organictin compound residue from the product compound will be facilitated.

In accordance with the present invention, tetrazolylbenzene compounds,particularly tetrazole derivatives having a hypotensive action based onangiotensin II--antagonizing activity, or production intermediatesthereof, can be obtained safely and in good yield. The invention is,therefore, of value as a commercial process for producingtetrazolylbenzene compounds.

The working examples and the reference examples are intended to describethe invention in further detail and should by no means be construed asdefining the scope of the invention.

EXAMPLE 1 Trioctyltin azide (Tri-n-octyltin azide)

In 30 ml of pure water was dissolved 10.19 g of sodium azide and thesolution was cooled to 8° C. Then, 50.0 g of trioctyltin chloride wasadded dropwise over a period of 10 minutes and the mixture was stirredat the same temperature for 2 hours. The reaction mixture was thenextracted with 88 ml of methylene chloride and further with 25 ml of thesame solvent, and the extract was washed with 25 ml of 10% aqueoussodium chloride solution and concentrated to provide 50.05 g oftrioctyltin azide.

IR(film): 2924, 2856, 2080, 1466cm⁻¹.

EXAMPLE 2 Tridodecyltin azide (Tri-n-dodecyltin azide)

To 3.18 g of magnesium was added 10 ml of the solution prepared bydissolving 30 g of dodecyl chloride in 60 ml of diethyl ether. To themixture was added two drops of bromine. The mixture was stirred for awhile. When reflux was started, the remaining solution was addeddropwise to the reaction mixture. After completion of the exothermicreaction, the reaction mixture was heated and stirred for 30 minutesunder reflux. The reaction mixture was cooled with ice, to which wasadded 5.29 g of stannic chloride. The mixture was stirred for one hourunder reflux. Diethyl ether was distilled off, and the residue wasstirred for 1.5 hour at 65° C. The reaction mixture was cooled and therewere added diethyl ether and 10% hydrochloric acid. The mixture wasshaken and was then left standing to form two layers. The organic layerwas separated and dried over calcium chloride, and then concentratedunder reduced pressure. To the concentrate was added 1.76 g of stannicchloride. The mixture was stirred for 3 hours at 200° C., once cooledand then stirred for further 3 hours at 200° C. The reaction mixture wascooled and then there was added methylene chloride. Insolubles werefiltered off, and the filtrate was washed with water, then dried overmagnesium sulfate, followed by concentration under reduced pressure. Theconcentrate was added dropwise to a solution of 3.44 g of sodium azidein 10 ml of water at 4° C., followed by stirring for 1.5 hour. Thereaction mixture was subjected to extraction with methylene chloride.The extract was dried over magnesium sulfate, and then concentrated toafford 21.59 g of tridodecyltin azide.

IR(film): 2928, 2856, 2080, 1468 cm⁻¹

EXAMPLE 3 Trioctadecyltin azide (Tri-n-octadecyltin azide)

A mixture of 20.0 g of trioctadecyltin chloride, 3.0 g of sodium azideand 40 ml of toluene was stirred at 120° C. for 6 hours. After cooling,100 ml of toluene was added to the reaction mixture. The toluene layerwas washed with water, dried over magnesium sulfate and concentratedunder reduced pressure to give 13.8 g of trioctadecyltin azide.

IR(film): 2128, 2056 cm⁻¹.

EXAMPLE 4 5-[2-(4'-methylbiphenyl)]-1H-tetrazole

A mixture of 4.85 g of 2-(4-methylphenyl)benzonitrile, 37.46 g oftrioctyltin azide (tri-n-octyltin azide) and 24 ml of toluene wasstirred at 125° C. for 8.5 hours. After cooling, the reaction mixturewas concentrated. To the residue was added 43 ml of ethanol as well asan aqueous solution of sodium nitrite (5.4 g/21 ml) and the mixture wasadjusted to pH 3 with hydrochloric acid. Then, 10 ml of ethyl acetateand 30 ml of n-hexane were added and the mixture was adjusted to pH 1with concentrated hydrochloric acid. After confirmation ofprecipitation, the mixture was adjusted to pH 3 with 30% aqueous sodiumhydroxide solution and the crystals were separated. At this junction,ferric chloride TS was added to a sample of the liquid phase but no redcolor developed. On drying, 4.45 g of crystals were obtained. The motherliquor was extracted with methylene chloride and the methylene chloridelayer was washed with water and extracted with 1N aqueous sodiumhydroxide solution. The sodium hydroxide layer was washed with methylenechloride and adjusted to pH 2.6 with concentrated hydrochloric acid andthe resulting crystals were separated. On drying, 1.56 g of crystalswere obtained. The crops of crystals were combined and dissolved in 25ml of ethyl acetate under heating and after 25 ml of n-hexane was addedthe solution was cooled. The resulting crystals were separated andwashed with 25 ml of ethyl acetate/n-hexane mixture (1:1). On drying,5.14 g of 5-[2-(4'-methylbiphenyl)]-1H-tetrazole was obtained. Yield87%. ¹ H NMR (CDCl₃) δ: 2.40 (3H, s), 7.16 (4H, dd), 7.40 (t)¹), 7.43(d)¹), 7.55 (2H, quintet-d), 8.15 (d)²), 8.19 (t)²)

Note: 1) 7.40 & 7.43 1H; 2) 8.15 & 8.19 1H IR(KBr): 1604, 1570, 1486,1452, 1400, 1248, 1162, 1080, 1052, 1010, 912, 826, 776, 756, 556, 522,450 cm⁻¹.

EXAMPLE 5 Methyl2-ethoxy-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole-7-carboxylate

A mixture of 13.0 g of methyl1-(2'-cyanobiphenyl-4-yl)methyl-2-ethoxybenzimidazole-7-carboxylate,47.1 g of trioctyltin azide (tri-n-octyltin azide) and 60 ml of toluenewas refluxed at 125° C. for 31 hours. After cooling, the reactionmixture was concentrated. To the concentrate was added 56 ml of ethanolas well as an aqueous solution of sodium nitrite (7.7 g/28 ml) and themixture was adjusted to pH 5 with concentrated hydrochloric acid. Then,31 ml of ethyl acetate was added. The mixture was further adjusted to pH1.1 with concentrated hydrochloric acid, diluted with 20 ml of n-hexaneand adjusted to pH 3.3 with 1N aqueous sodium hydroxide solution. Thecrystals were separated, washed with ethyl acetate/n-hexane mixture(1:3) and dried to provide 14.56 g of methyl2-ethoxy-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole-7carboxylate.Yield 100%. ¹ H NMR (CDCl₃) δ: 1.42 (3H, t), 3.56 (3H, s), 4.27 (2H, q),5.54 (2H, s), 6.70 (2H, d), 6.78-6.95 (4H, m), 7.28-7.33 (1H, m), 7.40(1H, dd), 7.56-7.66 (2H, m), 8.02-8.06 (1H, m)

IR(KBr): 1720, 1618, 1548, 1476, 1432, 1390, 1354, 1324, 1284, 1222,1134, 1042, 872, 840, 820, 780, 756 cm⁻¹.

EXAMPLE 6 5-[2-(4'-phthalimidomethylbiphenylyl)]-1H-tetrazole

A mixture of 3.00 g of 4-(2-benzonitrile)-benzylphthalimide, 13.3 g oftrioctyltin azide (tri-n-octyltin azide) and 15 ml of toluene wasstirred at 115°-120° C. for 29 hours. After cooling, the reactionmixture was concentrated. To the residue was added 16 ml of ethanol aswell as an aqueous solution of sodium nitrite (2.0 g/8 ml) and themixture was adjusted to pH 3.1 with concentrated hydrochloric acid.Then, 5 ml of ethyl acetate and 15 ml of n-hexane were added and themixture was cooled. The crystals formed were separated, washed with 30ml of n-hexane and dried to provide 3.51 g of5-[2-(4'-phthalimidomethylbiphenylyl)]-1H-tetrazole. Yield 100%. ¹ H NMR(CDCl₃) δ: 4.78 (2H, s), 7.9-8.0 (12H, m) IR(KBr): 1770, 1714, 1466,1436, 1396, 1346, 1090, 944, 768, 758, 718, 630, 530 cm⁻¹

EXAMPLE 72-Butyl-4-chloro-5-formyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole

A mixture of 2.11 g of2-butyl-4-chloro-5-formyl-1-(2'-cyanobiphenyl-4-yl)methylimidazole, 8.38g of trioctyltin azide (tri-n-octyltin azide) and 10 ml of toluene wasstirred at 120° C. for 18 hours. After cooling, the reaction mixture wasconcentrated. To the residue was added 10 ml of ethanol as well as anaqueous solution of sodium nitrite (1.3 g/5 ml) and the mixture wasadjusted to pH 3.3 with concentrated hydrochloric acid. The mixture wasdiluted with 20 ml of water and extracted with two 20 ml portions ofethyl acetate. The ethyl acetate solution was concentrated and theresidue was purified by chromatography on 30 g of silica gel (CH₂ Cl₂-MeOH). The active fraction was concentrated to provide 1.82 g of2-butyl-4-chloro-5-formyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole.Yield 73%. ¹ H NMR (CDCl₃) δ: 0.78-1.80 (9H), 2.53 (3H, t), 5.51 (2H,s), 6.9-8.0 (12H, m), 9.66 (1H, s) IR(KBr): 2964, 1668, 1518, 1466,1382, 1280, 758 cm⁻¹

EXAMPLE 82-Butyl-4-chloro-5-(hydroxymethyl)-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole

A mixture of 5 g of2-butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole,30.2 g of trioctyltin azide (tri-n-octyltin azide), 25 ml of toluene and1 ml of dimethylformamide was stirred for 24 hours at 115° C. innitrogen streams. The reaction mixture was, after cooling, concentrated,and there were added 40 ml of ethanol and a solution of 5.2 g of sodiumnitrite in 19 ml of water, whose pH was adjusted at 3.4 with conc.hydrochloric acid. The resultant mixture was subjected to extractionwith methylene chloride, and the extract was concentrated under reducedpressure. To the concentrate was added hexane, then resultingcrystalline precipitates were collected by filtration. The crystals werewashed with hexane, then dried to afford 5.27 g (yield 94.7%) of2-butyl-4-chloro-5-(hydroxymethyl)-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole.The NMR spectrum of the product was in good agreement with thatdescribed in J. Med. Chem., 1991, 34, 2525.

EXAMPLE 9 5-[2-(4'-methylbiphenyl)]-1H-tetrazole

A mixture of 1.50 g of 2-(4-methylphenyl)benzonitrile, 19.5 g oftridodecyltin azide (tri-n-dodecyltin azide) and 7 ml of toluene wasstirred for 37.5 hours at 120° C. The reaction mixture was, aftercooling, concentrated, and there were added 18 ml of ethanol, 1 ml ofmethylene chloride and 2.4 g of sodium nitrite dissolved in 9 ml ofwater, whose pH was adjusted at 3.4 with conc. hydrochloric acid. To themixture were added 2 ml of ethyl acetate and 100 ml of hexane.Insolubles were filtered off. The filtrate was shaken, then leftstanding to form two layers. The organic layer was subjected toextraction with 1N NaOH. The alkaline layer was adjusted at pH 3 withconc. hydrochloric acid, and then subjected to extraction with ethylacetate. The extract was concentrated, and there were added ethylacetate and hexane to cause crystallization. The crystals were collectedby filtration, washed with hexane and dried to afford 1.51 g (yield82.3%) of 5-[2-(4'-methylbiphenyl)]tetrazole. Spectrum data were in goodagreement with those in Example 4.

EXAMPLE 10 5-[2-(4'-Methylbiphenyl)]-1H-tetrazole

A mixture of 0.50 g of 2-(4-methylphenyl)benzonitrile and 13.6 g oftrioctadecyltin azide (tri-n-octadecyltin azide) was stirred for 13.5hours at 120° C. The reaction mixture was processed in substantially thesame manner as in Example 9 to afford 0.499 g (yield 81.6% ) of5-[2-(4-methylbiphenyl)]-1H-tetrazole. Spectrum data were in goodagreement with those in Example 4.

What is claimed is:
 1. A compound of the formula (R)₃ SnN₃, wherein R isn-octyl.